特殊环境微生物的次生代谢产物研究
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摘要
特殊环境来源的微生物的代谢途径独特,因而其次生代谢产物的化学结构新颖、种类繁多,是新活性先导化合物的重要来源。获得结构新颖的先导化合物是创新药物研究的关键,而能产生量大、结构新颖的次生代谢产物的“天才菌株”(Talented Strains)是获得新的先导化合物的前提保证。为了寻找抗肿瘤活性先导化合物,本论文采用活性追踪的方法开展了特殊环境的微生物的抗肿瘤活性代谢产物的研究工作。内容包括:“天才菌株”的筛选和发酵条件考察;抗肿瘤活性成分的追踪分离;单体化合物的结构解析;单体化合物抗肿瘤活性的初步评价。采用TLC和HPLC相结合的化学筛选方法,对43株活性红树林真菌和20株高盐真菌代谢产物的化学多样性进行了研究,从中选出6株真菌作为本论文的研究对象。
通过改变培养基、盐浓度等方法,研究了1株高产细胞松弛素类化合物的“天才菌”KLA03不同盐浓度下的次生代谢产物的差异。
采用海虾生物致死法和tsFT210细胞的流式细胞术筛选模型,以细胞周期抑制和细胞凋亡诱导以及坏死性细胞毒为活性指标,对48株海洋微藻进行了活性筛选,从中选出1株高活性的微藻作为本论文的研究对象。
在获得了目标菌株并考察了其培养条件后,对6株目标真菌(含3株Talented Strains)和1株微藻进行了大量发酵。对发酵产物运用萃取、薄层层析、(正相、反相)硅胶柱层析、LH-20凝胶柱层析、反相高压液相等分离纯化手段,从焦曲霉(Aspergillus ustus 094102)的代谢产物中分离得到42个化合物单体(1-42);从扩张青霉(Penicillium expansum 091006)中分离得到了16个单体化合物(43-58);从黄曲霉(Aspergillus flavus 092008)中分离得到8个单体化合物(59-66);从耐盐真菌柑桔青霉(Penicillium citrinum B-57)中分离得到了15个单体化合物(67-81);从耐盐真菌青霉(Penicillium sp. B-58)中分离得到了16个单体化合物(82-97),从真菌KLA03曲丽穗霉(Spicaria elegans)中分离得到了7个单体化合物(98-104),从金藻(Ruttnera spectabilis H55)中分离得到了2个单体化合物(105-106)。
继而,利用理化性质和波谱学方法(IR,UV,MS,NMR,CD)结合化学反应阐明了这106个化合物的化学结构,其中新化合物42个,包括:10个补身烷型倍半萜类化合物(1-11)、8个苯并呋喃类化合物(14-21)、6个蛇孢假壳素类二倍半萜烯类化合物(24-29)、6个简单苯的衍生物(34-39)、6个结构新颖的甲苯酚三聚体(43-48)、2个没药烷型倍半萜类化合物(49-50)、1个黄曲霉毒素类化合物(59)、2个结构新颖的二聚橘霉素类化合物(67-68)和1个不对称的二聚对羟基苯丙烯酸化合物(98)。已知化合物的结构类型还涉及二氧哌嗪类化合物(41, 54-55, 64, 82-87),吡喃类化合物(65, 88-91),蒽醌类化合物(63, 79-81),橘霉素及其衍生物(73-78),甾体类化合物(40, 57-58),三萜类化合物(56),tetiamic acid类化合物(72)和aspochalasin类化合物(101),类胡萝卜素类化合物(105)和脂肪族类化合物(106)。
利用MTT法、SRB法以及流式细胞术结合形态学检测的方法,在细胞水平上(A549和HL60)初步评价了单体化合物的抗肿瘤活性。从中筛选出了4个高活性的新化合物(18, 27, 28, 44):化合物18选择性地对HL60细胞表现出抑制活性其IC50值分别为0.13μM;化合物27对两种肿瘤细胞的IC50值分别为0.6和0.8μM;化合物28对两种肿瘤细胞的IC50值分别为2.4和1.7μM;化合物44对两种肿瘤细胞的IC50值分别为1.9和5.4μM。还筛选出8个具有中等抑制活性的新化合物(5, 7, 9, 24, 29, 43, 45, 47):化合物5对两种肿瘤细胞(A549和HL60)的IC50值分别为30.0和20.6μM;化合物7选择性地对A549表现出抑制活性的,其IC50值为10.5μM;化合物9选择性地对HL-60表现出抑制活性的,其IC50值为9.0μM;化合物24对两种肿瘤细胞的IC50值分别为15.1和7.0μM;化合物29对两种肿瘤细胞的IC50值分别为33.8和7.2μM;化合物43选择性地对HL60细胞表现出抑制活性其IC50值分别为15.7μM;化合物45选择性地对HL60细胞表现出抑制活性,其IC50值分别为18.2μM;化合物47选择性地对HL60细胞表现出抑制活性,其IC50值分别为20.8μM。
本文对六株特殊环境来源的真菌和一株微藻的次级代谢产物进行了系统研究,共分离鉴定了106个化合物的结构,包括新化合物42个,高活性新化合物4个,中等活性新化合物8个。本文研究为抗肿瘤新药的研究提供了重要的先导结构,并为海洋药用微生物资源的开发提供了重要的参考。
Microorganisms in extraordinary environments have special biogenetic pathway and have become an important source of bioactive secondary metabolites. A study was carried out to investigate the potential anti-tumor compounds derived from microorganisms in extraordinary environments. This dissertation describes the discovery of several new antitumor lead compounds produced by 6 strains of halotolerant fungi from mangrove ecosystems and salt marsh and 1 strain of microalga. Studies include screening of microbial talented strains to produce secondary metabolites with large yield and novel structure, fermentation studies, fractionation, structural elucidation and preliminary evaluation for anti-tumor activities of pure compounds.
Chemical diversity of 43 strains of mangrove fungi and 20 strains of salt marsh fungi with cytotoxic and antimicrobial activities were detected by TLC and HPLC methods. 6 strains including 3 talented strains were chosen as the working strains because of their large variety of metabolites. And one active strain was chosen from 48 strains of marine microalgae by brine shrimp lethality assay and cytotoxicity assay on tsFT210 cell lines.
Optimization of fermentation condition for talented strains was studied, and large-scale fermentation and preparation of the active fractions were performed to obtain the active fractions of the talented strains. Compounds were isolated and purified by means of solvent extraction, silica gel column chromatography, Sephadex LH20 column chromatography, and PHPLC. From fungus Aspergillus ustus 094102, 42 compounds (1-42) were isolated; from fungus Penicillium expansum 091006, 16 compounds (43-58) were isolated; from Aspergillus flavus 092008, 8 compounds (59-66) were isolated; from Penicillium citrinum B-57, 15 compounds (67-81) were isolated; from Penicillium sp. B-58, 16 compounds (82-97) were isolated; from Spicaria elegans KLA03, 7 compounds (98-104) were isolated; from Ruttnera spectabilis H55, 2 compounds (105-106) were isolated. Their structures were elucidated by physicochemical properties and spectral analysis (IR, UV, MS, NMR, CD, etc.). Among them, 42 new compounds were identified and structures belonged to drimane-type sesquiterpenoids (1-11), isochroman derivatives (14-21), ophiobolin-type sesterterpenoids (24-29), phenolic compounds (34-39), tricresol trimers (43-48), bisabolane-type sesquiterpenes (49-50), aflatoxin (59), citrinin drimers (67-68), and biphenyl compound (98). In addition, the types of the known compounds are involved in dipeptides (41, 54-55, 64, 82-87), pyran-2-one derivatives (65, 88-91), anthraquinones (63, 79-81), citrinin and derivatives (73-78), sterols (40, 57-58), triterpene (56), tetiamic acid (72), aspochalasin (101), carotenoid (105) and fatty acids (106).
The cytotoxicity against two cancer cell lines, A549 and HL60, were assayed by MTT, SRB and flow cytometry methods. As the results, new compounds 18, 27, 28 and 44 showed significant cytotoxicity with IC50 values of 0.13μM (HL-60), 0.6 and 0.8μM, 2.4 and 1.7μM, 1.9 and 5.4μM respectively; new compounds 5, 7, 9, 24, 29, 43, 45, 47 showed moderate cytotoxicity with IC50 values of 30.0 and 20.6μM, 10.5μM (A549), 9.0μM (HL-60), 15.1 and 7.0μM, 33.8 and 7.2μM (HL-60), 15.7μM (HL-60), 18.2μM (HL-60), 20.8μM (HL-60) respectively.
通过改变培养基、盐浓度等方法,研究了1株高产细胞松弛素类化合物的“天才菌”KLA03不同盐浓度下的次生代谢产物的差异。
采用海虾生物致死法和tsFT210细胞的流式细胞术筛选模型,以细胞周期抑制和细胞凋亡诱导以及坏死性细胞毒为活性指标,对48株海洋微藻进行了活性筛选,从中选出1株高活性的微藻作为本论文的研究对象。
在获得了目标菌株并考察了其培养条件后,对6株目标真菌(含3株Talented Strains)和1株微藻进行了大量发酵。对发酵产物运用萃取、薄层层析、(正相、反相)硅胶柱层析、LH-20凝胶柱层析、反相高压液相等分离纯化手段,从焦曲霉(Aspergillus ustus 094102)的代谢产物中分离得到42个化合物单体(1-42);从扩张青霉(Penicillium expansum 091006)中分离得到了16个单体化合物(43-58);从黄曲霉(Aspergillus flavus 092008)中分离得到8个单体化合物(59-66);从耐盐真菌柑桔青霉(Penicillium citrinum B-57)中分离得到了15个单体化合物(67-81);从耐盐真菌青霉(Penicillium sp. B-58)中分离得到了16个单体化合物(82-97),从真菌KLA03曲丽穗霉(Spicaria elegans)中分离得到了7个单体化合物(98-104),从金藻(Ruttnera spectabilis H55)中分离得到了2个单体化合物(105-106)。
继而,利用理化性质和波谱学方法(IR,UV,MS,NMR,CD)结合化学反应阐明了这106个化合物的化学结构,其中新化合物42个,包括:10个补身烷型倍半萜类化合物(1-11)、8个苯并呋喃类化合物(14-21)、6个蛇孢假壳素类二倍半萜烯类化合物(24-29)、6个简单苯的衍生物(34-39)、6个结构新颖的甲苯酚三聚体(43-48)、2个没药烷型倍半萜类化合物(49-50)、1个黄曲霉毒素类化合物(59)、2个结构新颖的二聚橘霉素类化合物(67-68)和1个不对称的二聚对羟基苯丙烯酸化合物(98)。已知化合物的结构类型还涉及二氧哌嗪类化合物(41, 54-55, 64, 82-87),吡喃类化合物(65, 88-91),蒽醌类化合物(63, 79-81),橘霉素及其衍生物(73-78),甾体类化合物(40, 57-58),三萜类化合物(56),tetiamic acid类化合物(72)和aspochalasin类化合物(101),类胡萝卜素类化合物(105)和脂肪族类化合物(106)。
利用MTT法、SRB法以及流式细胞术结合形态学检测的方法,在细胞水平上(A549和HL60)初步评价了单体化合物的抗肿瘤活性。从中筛选出了4个高活性的新化合物(18, 27, 28, 44):化合物18选择性地对HL60细胞表现出抑制活性其IC50值分别为0.13μM;化合物27对两种肿瘤细胞的IC50值分别为0.6和0.8μM;化合物28对两种肿瘤细胞的IC50值分别为2.4和1.7μM;化合物44对两种肿瘤细胞的IC50值分别为1.9和5.4μM。还筛选出8个具有中等抑制活性的新化合物(5, 7, 9, 24, 29, 43, 45, 47):化合物5对两种肿瘤细胞(A549和HL60)的IC50值分别为30.0和20.6μM;化合物7选择性地对A549表现出抑制活性的,其IC50值为10.5μM;化合物9选择性地对HL-60表现出抑制活性的,其IC50值为9.0μM;化合物24对两种肿瘤细胞的IC50值分别为15.1和7.0μM;化合物29对两种肿瘤细胞的IC50值分别为33.8和7.2μM;化合物43选择性地对HL60细胞表现出抑制活性其IC50值分别为15.7μM;化合物45选择性地对HL60细胞表现出抑制活性,其IC50值分别为18.2μM;化合物47选择性地对HL60细胞表现出抑制活性,其IC50值分别为20.8μM。
本文对六株特殊环境来源的真菌和一株微藻的次级代谢产物进行了系统研究,共分离鉴定了106个化合物的结构,包括新化合物42个,高活性新化合物4个,中等活性新化合物8个。本文研究为抗肿瘤新药的研究提供了重要的先导结构,并为海洋药用微生物资源的开发提供了重要的参考。
Microorganisms in extraordinary environments have special biogenetic pathway and have become an important source of bioactive secondary metabolites. A study was carried out to investigate the potential anti-tumor compounds derived from microorganisms in extraordinary environments. This dissertation describes the discovery of several new antitumor lead compounds produced by 6 strains of halotolerant fungi from mangrove ecosystems and salt marsh and 1 strain of microalga. Studies include screening of microbial talented strains to produce secondary metabolites with large yield and novel structure, fermentation studies, fractionation, structural elucidation and preliminary evaluation for anti-tumor activities of pure compounds.
Chemical diversity of 43 strains of mangrove fungi and 20 strains of salt marsh fungi with cytotoxic and antimicrobial activities were detected by TLC and HPLC methods. 6 strains including 3 talented strains were chosen as the working strains because of their large variety of metabolites. And one active strain was chosen from 48 strains of marine microalgae by brine shrimp lethality assay and cytotoxicity assay on tsFT210 cell lines.
Optimization of fermentation condition for talented strains was studied, and large-scale fermentation and preparation of the active fractions were performed to obtain the active fractions of the talented strains. Compounds were isolated and purified by means of solvent extraction, silica gel column chromatography, Sephadex LH20 column chromatography, and PHPLC. From fungus Aspergillus ustus 094102, 42 compounds (1-42) were isolated; from fungus Penicillium expansum 091006, 16 compounds (43-58) were isolated; from Aspergillus flavus 092008, 8 compounds (59-66) were isolated; from Penicillium citrinum B-57, 15 compounds (67-81) were isolated; from Penicillium sp. B-58, 16 compounds (82-97) were isolated; from Spicaria elegans KLA03, 7 compounds (98-104) were isolated; from Ruttnera spectabilis H55, 2 compounds (105-106) were isolated. Their structures were elucidated by physicochemical properties and spectral analysis (IR, UV, MS, NMR, CD, etc.). Among them, 42 new compounds were identified and structures belonged to drimane-type sesquiterpenoids (1-11), isochroman derivatives (14-21), ophiobolin-type sesterterpenoids (24-29), phenolic compounds (34-39), tricresol trimers (43-48), bisabolane-type sesquiterpenes (49-50), aflatoxin (59), citrinin drimers (67-68), and biphenyl compound (98). In addition, the types of the known compounds are involved in dipeptides (41, 54-55, 64, 82-87), pyran-2-one derivatives (65, 88-91), anthraquinones (63, 79-81), citrinin and derivatives (73-78), sterols (40, 57-58), triterpene (56), tetiamic acid (72), aspochalasin (101), carotenoid (105) and fatty acids (106).
The cytotoxicity against two cancer cell lines, A549 and HL60, were assayed by MTT, SRB and flow cytometry methods. As the results, new compounds 18, 27, 28 and 44 showed significant cytotoxicity with IC50 values of 0.13μM (HL-60), 0.6 and 0.8μM, 2.4 and 1.7μM, 1.9 and 5.4μM respectively; new compounds 5, 7, 9, 24, 29, 43, 45, 47 showed moderate cytotoxicity with IC50 values of 30.0 and 20.6μM, 10.5μM (A549), 9.0μM (HL-60), 15.1 and 7.0μM, 33.8 and 7.2μM (HL-60), 15.7μM (HL-60), 18.2μM (HL-60), 20.8μM (HL-60) respectively.
引文
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